PROJECT SUMMARY This application entitled ?Preclinical development of mGlu2 positive allosteric modulators to treat substance use disorders? is in response to PAR-13-270 ?Grand Opportunity in Medications Development for Substance-Use Disorders?. Cocaine addiction remains a major public health problem without any treatment options. Cigarette smoking, attributable primarily to the addictive properties of nicotine, is one of the largest preventable causes of morbidity and mortality worldwide. Currently available FDA-approved medications for nicotine cessation have limited efficacy and adverse side effects, resulting in low compliance rates. Thus, there is a substantial need for new and more efficacious anti-addiction medications. Experimental evidence indicates that the positive reinforcing effects of cocaine/nicotine and reinstatement of cocaine- or nicotine-seeking behavior following withdrawal are related to increases in glutamate transmission in the brain. Furthermore, adaptations in glutamatergic transmission produced by repeated drug exposure to cocaine or nicotine contribute to the maintenance of addictive behaviors. Therefore, targeting reduction of glutamatergic transmission is a rational strategy to treat both the maintenance of drug use and prevent relapse. Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 2 (mGlu2) have been shown by us and others to decrease both cocaine and nicotine self-administration and cue-induced reinstatement of drug seeking in a valid animal models of reinforcement and relapse. Thus, mGlu2 PAMs may represent a new class of drugs for the treatment of substance use disorders. We have developed two distinct chemical series of potent and selective mGlu2 PAMs with excellent drug-like properties including oral bioavailability and brain penetration that decrease cocaine and nicotine self-administration in rats. Therefore, the overall objective of this project is to develop an orally active mGlu2 PAM as a clinical drug candidate for the treatment of cocaine and/or nicotine addiction in humans. Accordingly, our Specific Aims are: 1. Complete the characterization of current lead clinical candidate mGlu2 PAM SBI-0069330 and identify one or more back-up candidates; 2. Determine the in vivo efficacy of candidate mGlu2 PAMs in rat models of cocaine/nicotine reinforcement and relapse; and 3. Determine the absorption, distribution, metabolism, excretion (ADME), pharmacokinetic (PK), safety, and toxicological profile of the lead clinical candidate mGlu2 PAM to support filing an investigational new drug (IND) application. To achieve these Aims, we have assembled a multidisciplinary team of experienced investigators who are experts in their respective fields with a proven track record in drug discovery and mGlu research. The infrastructure required for undertaking the proposed work is fully established and operational. The lead compound has been identified, and back-ups are ready for optimization, selection, and preclinical studies. Thus, by the end of the study period, we expect to deliver a small molecule mGlu2 PAM clinical candidate for the treatment of cocaine and nicotine addiction in humans.